Chapter one of your genetics
textbook will probably define "dominant" and "recessive", and that’s fine. But
it's not enough to get a handle on what’s really going on genetically with our
dogs (or ourselves, for that matter). Everything in the real world will
make more sense if we take a moment to look at the genes themselves and the
complications that arise to alter our simple Mendelian expectations.

First, what is a gene?

A gene is a length of DNA that
codes for a particular polypeptide. A polypeptide is a piece of a protein.
Polypeptides, and thus proteins, are made up of small molecules called amino
acids. Put
the right set of amino acids together the right way and you get a protein. Put
them together the wrong way and you get, frequently, a nonfunctional
or only partially functional protein. For example, you might either have an
allele that codes for functional tyrosinase, an enzyme necessary to make
melanin; or else you might have an allele (the albino allele) that codes for a
nonfunctional tyrosinase protein. Failing to produce functional tyrosinase
leads to a failure to produce melanin later down a particular metabolic pathway,
and poof! You are albino. The
important point is this:

Genes code for proteins, not
directly for traits.

This matters because complicated
traits, not to mention plenty that look simple, are probably influenced by a lot
of different genes (they are polygenic; the genes involved are sometimes
called polygenes). Even “simple” traits may not turn out to be all that simple
once you really look at them. The common human genetic disease cystic fibrosis
is caused by a failure of protein “channels” (cystic fibrosis transmembrane
conductance regulators) in the membranes of certain cells to function properly
in the transport of chlorine ions, which in turn means that the movement of
water across those membranes does not happen properly. Although this disease
is thought of as a simple recessive, and is presented that way in every general
biology text on the market, it’s not so simple in the real world.
Understanding the molecular biology behind gene action lets you see genes as
they really are, rather than as magic wands that -- poof! -- create random
effects. This lets you make reasonable guesses about the genetic action
behind specific traits you observe in your own dogs.

How does cystic fibrosis work in
the real world? The CFTR gene responsible for
making the particular channel protein described above is subject to over a thousand described
mutations (!) (http://www.genet.sickkids.on.ca/cftr/), many of which can cause clinical cystic fibrosis. The most common
mutation that leads to cystic fibrosis is a deletion of three nucleotides at
position 508 in the gene, but several different clinical forms of cystic
fibrosis exist – different clinically because they are different genetically (http://www.niddk.nih.gov/health/endo/ pubs/cystic/cystic.htm).
And this disease is presented as 'simple'! In the real world, verylittle is as simple as your average textbook implies.

Here are the basic “extra
complications” with
which anyone breeding dogs ought to be familiar:

Incomplete (partial) dominance

In complete
dominance, both GG and Gg (for example) animals are gray – equally
gray – and there is no way to tell what their genotypes just by looking at
them. Only gg animals are not gray. If dominance is incomplete, then
GG animals would be gray, gg animals would be non-gray, and Gg
animals would be intermediate in phenotype. What is usually happening in this
kind of situation is probably that the dominant allele in a heterozygote Gg
is making enough of a functional protein to partially but not fully compensate
for the existence of the recessive allele. (In real life, G appears
to be completely dominant to g.)

An example
in the real world of
incomplete dominance is seen with the chinchilla dilute which appears to be
present in dogs: CC animals express full pigment; cchcch
animals would be cream or white, and Ccch
animals have yellow (phaeomelanin) but not black (eumelanin) pigment diluted.
In horses this gives us the chestnut – palomino – cream (cremello) series of
colors. The chestnut horse has undiluted phaeomelanin, the palomino has
some phaeomelanin, and the cream has virtually no phaeomelanin. In dogs, the chinchilla dilute probably gives us black-and-silver
miniature Schnauzers by diluting the tan points on an otherwise black-and-tan
dog. This gene is probably responsible for some of the cream and white
breeds, too.

There is no such
thing as a “carrier” for an incompletely dominant trait, as heterozygotes stand
out phenotypically from homozygous dominants as well as homozygous recessives.

Probably there is some incomplete dominance in the spotting series for
dogs, such that Ssp animals have more white
markings than SS animals, spsw
have more white markings that spsp,
and so forth.

Codominance

Where incomplete
dominance gives us heterozygotes with intermediate phenotype, codominance gives
us heterozygotes which express both dominant and recessive traits at the same
time. The classic example is seen in human blood types: You can be type A
(genotype AA), type B (genotype BB) or type AB (genotype AB).
In codominant traits, two different alleles are probably coding for different
proteins, both of which are functional, but in different ways. There are
probably quite a few codominant traits, but relatively few which are visible in
simple phenotypic terms.

Lethality

In this unhappy
situation, one genotype is taken out of the picture because it suffers such
severe problems that it dies. Lethals need not be literally all-the-way
lethal to have a substantial effect on a breed. In dogs, merle can act
as a
deleterious dominant, although not actually lethal in most cases: Mm
animals show merle coloring where they would otherwise have been black, mm
animals are non-merle, and MM animals are frequently blind or deaf or both,
as well as mostly white.
I've seen sources which indicate that the deleterious effects of the MM genotype seem to be partially or wholly
offset if the dog has no other white markings – a MM sheltie is likely to
have serious problems, it is said, whereas apparently a MM Dachshund is not. On
the other hand, I've also seen sources which indicate that merle Dachshunds are
not free of problems, so I don't know.

The hairless mutation that creates the special coat variation in Chinese Crested
Dogs is a lethal allele. Breed two hairless Cresteds together and you
should get, on average, 1/4 puffs, 1/2 hairless, and 1/4 dead puppies (which I
believe are invisible, since they vanish before birth). Breed a hairless
with a puff and you should get 1/2 hairless and 1/2 puffs (and bigger litters,
since none are killed by doubling up on the hairless allele). This is a
difficult mutation to talk about genetically because the hairless form is
dominant to the powderpuff (normal fully coated form), but the lethality itself
acts in a recessive manner -- you need to have two HH (hairless) alleles for the
puppy to die. This kind of trait might be referred to as an incomplete
dominant trait with recessive lethality . . . though it would be nice if there
was a more concise and clear way to put that!

The hairless
mutation possessed by American Hairless Terriers is a different mutation and not
lethal, btw. Two of the (at least
four) pinto patterns seen in horses are lethals. The "extra"
harlequin gene that, in combination with merle, creates the harlequin coat
pattern in Great Danes, may also be a lethal (harlequin Danes are
probably double heterozygotes: MmHh). Breeding around lethals
requires basic familiarity with genetics.

Sex linkage (X linkage)

This simply means that the trait in question is controlled by a gene located on
the X chromosome (very few genes are present on the small Y chromosome, other
than the ones that say “be male”; this implies that the special attention
sometimes paid to the tail-male line in a pedigree is misplaced, since the Y
chromosome is the only one which must be passed down this line). Since dogs have 39 pairs of chromosomes
(compared to the human 23), we would not expect a very large percentage of
traits to be located on the X chromosome (which implies that the tail-female
line in a pedigree is also not particularly important). However, some forms of
hemophilia in dogs (hemophilia A and B) are thought to be X-linked, as is
hemophilia in humans, of course.

If a trait is
X-linked and also deleterious, you would expect most of the puppies produced
with the trait to be male. This is because the most typical situation would be
a normal but carrier dam bred to a normal sire – both parents would be phenotypically
normal, but half the sons (on average) would be affected by the trait (and half the daughters
would be carriers).

If the trait is not
significantly deleterious (such as color-blindness in humans), then you would expect affected males to
be used in breeding (since no one would care about the trait) and the ratio of
affected males and females would probably be closer to even, although even then
you would expect more affected males than females.

The best way to show
X-linkage when working with such a trait on paper is probably by putting the gene in question on the X
chromosome: XAXawould be a carrier female; XaY
an affected male, for example. If you do Punnett squares to predict the
results of a cross, using this kind of notation keeps the "empty space" on the Y
from getting lost.

Linkage

Genes are said to be “linked” when they are physically located near one another
on the same chromosome. Linkage becomes important because linked genes do
not assort independently. Linkage is one way you can get normal
Mendelian ratios messed up when you do a cross. You might get
double dew claws assorting with white color, for example, even though the traits
do not directly influence each other. (I just made that up; there's no
reason to expect that particular linkage to occur). “Linkage groups” are
groups of genes that are all close to one another. Some genetic tests test
directly for genes that are responsible for a problem, but others are linkage
tests that test for genes linked to the genes that actually cause the
problem. Linkage is never absolute; it can be broken by crossing over
between homologous pairs of chromosomes
when gametes (sperm or eggs) are formed. So genetic tests that depend on
linked genes will yield some percentage of false negatives and false positives.
Repeating the test in this case would repeat the false result. How high a
percentage of false results there is depends on how tightly the genes are
linked. The labs that do the tests would know how high a percentage of
false results to expect for a particular test.

Epistasis / hypostasis

Epistasis is a term
used to refer to one gene acting “dominant” to a different gene at a different
locus. Note that this is not one allele being dominant to another in the same
gene series, but one gene altering the effect of another entirely different gene. A good example in
dogs is the ee genotype at the extension locus creating a clear
red or yellow color regardless of what alleles are present at the agouti
locus. Thus Blenheim cavaliers are black-and-tan at the agouti locus,
but expression of the black pigment in their coats is suppressed by the red dilute ee.
In this case, the agouti locus would also be said to be hypostatic
to the extension locus.

In high
school, generally students are told that brown eyes are dominant to blue, thus
leading to the more clueless teachers informing brown-eyed students with both
parents blue-eyed that they must have been adopted or the product of adultery.
In fact, human color genetics is not nearly as straightforward as dog color
genetics, but the insistence on treating it as though is leads to students being
subjected to this stupid and harmful idea by ignorant teachers. Multiple
genes and interactions between them show us how easy it is for brown to be
dominant to blue and yet for blue-eyed parents to give rise to brown-eyed
children. For example, suppose that AA or Aa means brown eyes, with
aa
giving the blue-eyed phenotype. But in addition, also say that BB or
Bb at
a separate gene also codes for brown eyes, with bb also giving the
blue-eyed phenotype. So blue is recessive in both cases, right? But
let's say that either aa or bb will give a child blue eyes,
regardless of what's going on at the other locus.

Then this kind
of cross, aaBb x Aabb, is between two blue-eyed parents. But there is a
1/4 chance per child conceived that the child will have brown eyes. Or say
the parents are aaBB x AAbb -- they still both have blue eyes, but
now every single one of their children will have brown eyes.

In
fact, something like this system is thought to control blue-vs-brown eyes in
humans, with at least one more gene acting to contribute green. Nobody
knows (I think) how you get gray or hazel eyes, so the situation is still more
complicated than this in real life.

Pleiotropy

When one gene
influences more than one trait, it is said to be pleiotropic. Thus the merle
dilute in dogs not only turns black areas into a patchwork of black and gray, it
also can influence ear and eye development, particularly if homozygous.
"Extra" effects need not be deleterious. The cystic fibrosis allele not only
causes disease in its homozygous state, but in its heterozygous state also protects
against respiratory disease.

Polygeny

When many genes
influence one trait, the trait is said to be polygenic (or multifactorial). The
two terms are used almost interchangeably in practice, although “multifactorial”
is really meant to indicate that part of the influence on the trait comes from
non-genetic environmental factors, whereas “polygenic” refers only to genetic
factors. In the real world, it is typical for polygenic traits, such as
temperament and hip dysplasia, to show environmental effects. This is not
universal: the construction of the front assembly in dogs is certainly polygenic, but as far as
I know is not thought to be affected by environmental factors. Usually.
Much. I mean, horrendously bad nutrition could give some poor creature
rickets or otherwise interfere with its growth, which would certainly affect the structure of the front, and that would
be environmental influence, obviously.

However, a
reasonable rule of thumb is:

If a trait is both
complicated anatomically and affected by environmental factors, it is very
likely polygenic. Gastric torsion and bloat is an excellent example of
this kind of trait because a tendency to bloat depends on, first, the
construction of the chest and abdomen -- complicated anatomically -- and then on
the temperament of the dog (shy dogs are more likely to bloat) and whether the
food dish is raised (if so, the dog is more likely to bloat).
Although we don't actually knowfor a fact the mode of inheritance
for this problem, it therefore looks an awful lot like a polygenic trait.

In contrast, if a simple metabolic
pathway is easy to visualize for a trait and it does not seem to be affected by
environmental factors, it is more likely to be genetically
simple – especially if the same or similar traits are known to be simple in
other breeds or other species. Metabolic disorders that depend on the loss
of one functional enzyme, such as copper toxicosis, are perfect examples of
this. So is the red color in Cavaliers. It doesn't much matter what
you do with a Cavalier's environment: red dogs are red and black ones are
black.

Two common models for
polygeny are additive polygeny and threshold polygeny.

Additive polygeny
would work like this: Suppose that each of nine genes adds a “dose” of pigment
when present in the dominant form, but not when recessive. Then an animal with
a AABBCcddEEFfGGHHii genotype would have very dark pigment (although not quite
as dark as possible), whereas a aabbCcddEEffggHhii animal would have very light
pigment (although not as light as possible). When plotted on a graph, the
possible genotypes for this trait would yield a bell-shaped (normal) curve, with
most of the animals being intermediate and a “tail” out towards the extremes on
both sides. You could, as a breeder, select for either extreme, but it
would not be nearly as easy to achieve consistent dark pigment in this situation
as it would if pigment was controlled by a simple one- or two-gene system.

Traits such as
pigment modifiers, height, some kinds of coat texture, and intelligence are easy to visualize
as additive traits. Eye color in dogs is also thought to work this way.
At least one breeder has suggested that in her experience, genes that contribute
darker eye pigment are likely to be recessive (http://www.netpet.batw.net/articles/index.html,
and scroll down to find the comments on eye color -- a lot of the articles at
this site are good).

Threshold polygeny
would work like this: suppose that six genes control the development of hip
dysplasia, in such a way that at least three of the genes must be homozygous
recessive before any degree of dysplasia exists, and after that more recessive
alleles mean the dysplasia is likely to be progressively worse. (There is
no theoretical reason to make recessive genes the bad guys; I'm just doing it
that way for the sake of simplicity.

The three-gene requirement
would then be the “threshold” that flips a switch and determines whether dysplasia is
present at all; the other alleles plus environmental factors then determine how
severe the dysplasia will be. Thus an animal with a AaBbCcDdEeFf possesses
lots of alleles that could contribute to dysplasia, but is itself normal. It can, and
probably will, pass on at least some deleterious alleles to its offspring. Remember
that each gamete gets one allele of each pair -- in
the worst case, this dog could make a gamete that contained all recessive (abcdef) alleles, passing on
a huge load of deleterious alleles to a puppy (there would be a (1/2)6
chance of it doing so, or a 1/64 chance, which is very small, but it could
happen. In fact, if this was a popular sire and produced, say 64 puppies
in one year, then the chances that one puppy would get this combination
of alleles would be very high.).

You can usually assume, when faced with a polygenic trait, that both parents of
an affected animal contributed some deleterious alleles. Their
contributions need not, however, have been equal. This is easy to see with
something like the following:

Dam: AabbccDdEe - normal
Sire: AaBbCcDDEE - normal

Offpring: aabbccDdEe -- affected
(moderately)

In this case, the dam contributed
five deleterious recessive alleles, while the sire only contributed three.

Models like this seem
to have reasonable predictive power when applied to the way many polygenic
traits are inherited in dogs. It's important to assess the siblings of
breeding animals in order to make the best guess possible about the genetic
quality of the animals you keep to breed, because looking at the whole family
makes it easier to assess how many deleterious alleles are likely to be floating
around in the family. More on that in Practical Genetics for the Breeder.

Stuff on the borderline

A single-gene trait
is simple; a polygenic trait is complex. Sometimes traits fall in between
simple and complex. One form of epilepsy in Welsh Springer Spaniels and
Standard Schnauzers is evidently controlled by two genes, both of which must be
homozygous recessive for epilepsy to occur – and one of the genes appears to be either on
the X chromosome or possibly is part of the mitochondrial DNA (!). This is why
most epileptic animals in these breeds are male. Probably more traits on the borderline between simple and complex will be
discovered as we learn more about the genetic control of problems in dogs.

Trinucleotide repeat disorders
(stuttering genes)

Nucleotides are the
basic building blocks of DNA and RNA. Codons are sets of three nucleotides
which code for particular amino acids (which are themselves the building blocks
of proteins). Trinucleotide repeat disorders are caused by the insertion of
long sequences of repeated codons in a sequence of DNA. There are
fourteen such disorders known in humans so far. Of these, Huntington’s
disease
is one of the best known. Normally the Huntington’s gene contains about
26 CAG codons. In people with Huntington’s disease, this number has been
expanded to 40 or 100 or even more repeats of this codon. The same CAG
trinucleotide also is involved in eight other known disorders, all of which,
like Huntington’s, involve progressive degeneration of nerve cells starting at a
relatively advanced age.

Fragile X syndrome in
humans is another trinucleotide repeat disorder, this one involving expansion of
a series of CGG repeats on the FMR-1 gene on the X chromosome.

Trinucleotide repeat
disorders frequently are inherited in a weird way. Sometimes, as in Fragile X,
the number of repeats goes up when the affected allele is passed from mother to
child, but not when the affected allele is passed from father to child (this may
work the other way ‘round for some disorders); and the number of repeats expands
sharply once the gene is past a certain number of repeats. Usually the disorder
is worse the more repeats are present -- symptoms are more severe or are
expressed earlier in life, usually both. Thus a trinucleotide repeat disorder
might
"look" X-linked or Y-linked, even when it’s not. Even weirder, it is likely to increase in
severity and penetrance over generations in a family. It may “look” recessive
when it first occurs in a family, but then “look” more and more dominant as
generations pass.

No trinucleotide
disorders have been described in dogs, yet, but I wouldn't be surprised if that
changed -- and having a picture in the back of your head about what to expect of
such a problem might make it easier to spot if such a problem came to light.
Besides, trinucleotide repeats are interesting. Links below.

Incomplete penetrance

If all the aa
individuals in a population (breed, species) show the aa phenotype, then
penetrance is complete and the breeder’s life is easy. (Easier, anyway.) If
some of the genotypically aa individuals show a A- phenotype, then
penetrance is incomplete (and the same, of course, if some A- individuals
show the aa phenotype). If penetrance is low enough, we would start
looking for other genes influencing the trait and we would at that point stop
thinking of the trait as genetically simple and begin to think of it as probably
polygenic or multifactorial.

Although incomplete
penetrance is common, it should not be used as a catch-all explanation for
failure of a trait to show expected Mendalian patterns. Traits that fail to
follow Mendalian expectations need to be assessed for other possible
complexities, especially polygeny.

Variable expressivity

Variable expressivity
is also common. This may merely mean that not all affected individuals are
affected to the same degree. Thus some animals with Von Willebrand’s syndrome
will be much sicker than others, for example. In the extreme case, this
would grade into incomplete penetrance as animals with the least severe
expression of the problem might be clinically normal, even though possessing the
"affected" genotype. Or, possibly, the same underlying genetic system
might give rise to syndromes that appear, on the surface, completely different,
such as obsessive-compulsive behavior in some individuals and skin disorders in
others.Nickolas Dodman suggests in one of
his books that a single problem with zinc and/or copper metabolism might give
rise to all kinds of problems -- including an awful skin condition called lethal
acrodermatitis and a range of obsessive behavior problem -- in bull terriers. This, too, could be described as variable
expressivity.

In a different way, if what you see on the outside is variable expression of symptoms,
this
might also indicate that the underlying genetic causation is different for animals
that show similar symptoms. Thus epilepsy created by the two-gene system
described above may be found mainly in males, usually first occur between 1 and
3 years of age, and involve infrequent but severe grand mal seizures that are
controllable with Phenobarbital; whereas epilepsy created by a different
mechanism might be evenly distributed between the sexes, normally show itself
between four months and a year of age, and involve frequent but less serious
seizures that do not respond well to medication; while yet a third epileptic
syndrome might mainly express itself as obsessive “fly-biting” behavior.

Syndromes which
appear grossly similar but vary
widely in age of onset, severity, and exact symptoms should probably be
suspected of being due to different underlying genetic systems, particularly if
the symptoms fall into two or more relatively discrete categories. On the
other hand, syndromes which appear different but could all be affected by a
problem with a particular metabolic or developmental pathway should be suspected
of being caused by the same underlying genetic factors.

Phenocopies

Many traits which can
be created by genetic systems can also be created by non-genetic causes, such as
exposure to toxins or traumatic injury. Thus, epilepsy may be caused by
diseases that involve a high fever, such as distemper; exposure to various
toxins; or a blow to the head. In these cases, the epilepsy could correctly be
referred to as a phenocopy. It can be difficult to distinguish phenocopies from
genetic problems. If occurrence of a problem in a breed is rare, sporadic and
unpredictable, and especially if the problem does not appear to be associated
with any particular line or environment, then it may be due to random
environmental or developmental effects and not to any underlying genetic problem.

Monosomies, Trisomies, and
Uniparental Disomies

Usually an individual gets one chromosome of each homologous pair from its
mother and one from its father. An egg cell thus (for dogs) has 39
chromosomes, and so does a sperm cell, and you put the two together and get 78
chromosomes (in 39 pairs). This is how it's supposed to work. In the
real world, accidents happen.

If chromosomes do not separate normally during meiotic cell division, by which
egg and sperm cells are formed, than you can get a gamete (egg or sperm
cell) which does not have the normal number of chromosomes. This is not
normally good for the puppy formed from that gamete. A monosomy occurs
when an individual gets only one chromosome of a pair rather than two (it would
have 77 chromosomes total). In humans, Turner syndrome occurs when an
embryo gets one X chromosome from one parent and nothing to match up with it
from the other (it is XO rather than XX or XY). This embryo will grow into
a female baby, and the baby will be born alive, but she won't be normal.
She will be sterile, short, with abnormal neck weakness.

Another possibility, again resulting from an error during meiosis, is that an
embryo will get two copies of one chromosome from one parent and one from the
other, three copies total. This is called a trisomy. In humans,
trisomy 21 (three copies of chromosome 21) causes Down syndrome. There are
other viable trisomies, but none as common as Down syndrome.

A third possible abnormality, even more interesting than either of the above,
occurs when an embryo receives two chromosomes from one parent and nothing from
the other. This is called a uniparental disomy, and when it happens there
are usually developmental effects, because different genes on a chromosome tend
to be activated when you get it from your mother versus when you get it from
your father. Therefore certain genes won't work normally if you get both
copies of a chromosome from one parent. Isn't that interesting?